Simvastatin reduces circulating oxysterol levels in men with hypercholesterolaemia

Irundika H.K Dias,Ivana Milic,Gregory Y.H Lip,Andrew Devitt,M Cristina Polidori,Helen R Griffiths

doi:10.1016/j.redox.2018.02.014

Abstract

Oxysterols (OHC) are biologically active cholesterol metabolites circulating in plasma that may be formed enzymatically (e.g. 24S-OHC, 25-OHC and 27-OHC) or by autoxidative mechanisms (e.g. 7-ketocholesterol, 7β-OHC and 25-OHC). Oxysterols are more soluble than cholesterol and are reported to exert inflammatory, cytoprotective and apoptotic effects according to concentration and species. Esterified oxysterols have been analysed in people with dementia and cardiovascular diseases although there is no consistent relationship between oxysterol esters and disease. However, oxysterol esters are held in lipoprotein core and may not relate to the concentration and activity of plasma free oxysterols. Methodological limitations have challenged the analysis of free oxysterols to date.We have developed a fast, sensitive and specific quantitative LC-MS/MS, multiple reaction monitoring (MRM) method to target five oxysterols in human plasma with analyte recoveries between 72% and 82% and sensitivities between 5 and 135 pg/ml. A novel method was used to investigate the hypothesis that simvastatin may reduce the concentrations of specific plasma free oxysterols in hypercholesterolaemia.Twenty healthy male volunteers were recruited (aged 41–63 years); ten were asymptomatic with high plasma cholesterol > 6.5 mM and ten were healthy with normal plasma cholesterol (< 6.5 mM). Simvastatin (40 mg/day) was prescribed to those with hypercholesterolaemia. Plasma samples were taken from both groups at baseline and after three months. Simvastatin reduced plasma cholesterol by ~35% (p < 0.05) at the end of three months.Oxysterols generated by autoxidation (but not enzymatically) were elevated up to 45 fold in hypercholesterolaemic midlife men. Plasma oxysterols were restored to those of healthy controls after simvastatin intervention suggesting that autoxidation is either prevented by simvastatin directly or that autoxidation is less prevalent when plasma cholesterol concentrations are within the normal range.

Highlights

The epsilon 4 allele of apolipoprotein E (ApoE) remains the strongest genetic risk factor for dementia [1, 2]; it is the lowest affinity ApoE isoform for cholesterol uptake by the lipoprotein receptor
We have investigated the hypothesis that simvastatin treatment in hypercholesterolaemia may reduce the concentrations of specific plasma oxysterols
The method described here for the simultaneous detection of five oxysterols has been optimised for analysis of non-esterified plasma oxysterols through a simple solid phase preparative procedure

Summary

Introduction

The epsilon 4 allele of apolipoprotein E (ApoE) remains the strongest genetic risk factor for dementia [1, 2]; it is the lowest affinity ApoE isoform for cholesterol uptake by the lipoprotein receptor. Several modifiable vascular risk factors in midlife are associated with the development of dementia decades later, including smoking and hypercholesterolaemia [3,4,5]. Independent studies have confirmed that statins are effective at reducing the risk for dementia in later life by 25-50% [6, 7]. These observations have led to the suggestion that modification of cholesterol metabolism in midlife may reduce later risk for dementia. We have previously shown that oxidised low density lipoprotein (oxLDL) is associated with impaired cognition in Alzheimer’s disease (AD), the most common form of dementia [8, 9]. Lipids extracted from oxLDL are pro-oxidant, neurotoxic and pro-inflammatory in a blood-brain barrier model [10, 11]

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Results

Conclusion